Bidirectional pain control by spinal noradrenaline via astrocyte-neuron interactions

Abstract

Pain transmission in the spinal dorsal horn (SDH) is regulated by descending neuronal pathways from the brain, such as noradrenergic (NAergic) neurons from the locus coeruleus. While it is known that spinal NA produces an antinociceptive effect, we have recently shown that NA has an ability to produce pain hypersensitivity via Hes5expressing SDH astrocytes. However, the mechanism underlying the bidirectional effect of spinal NA remains unknown. In this study, we showed that while intrathecal injection of NA at a low dose (NA low ) induced pain hypersensitivity via α 1A -adrenergic receptors (α 1A -ARs) in Hes5 + astrocytes, the hypersensitivity was not observed by intrathecal high-dose NA (NA high ). The effect of NA high was also mediated by activation of inhibitory interneurons via α 1A -ARs. We found that NA high also activated β 1 -ARs in astrocytes that suppressed the astrocytic α 1A -ARs-mediated effect. However, if α 1A -ARs are expressed in inhibitory interneurons, why does NA low produce pain hypersensitivity?We further found that activation of astrocytic α 1A -ARs increased release of adenosine, a factor that suppresses inhibitory interneurons. Therefore, our findings indicate that NA bidirectionally modulates pain transmission via astrocyte-neuron interactions in a concentration-dependent manner.